Asthma and other respiratory diseases have long been treated by the inhalation of appropriate medicament. For many years the two most widely used and convenient choices of treatment have been the inhalation of medicament from a drug solution or suspension in a pressurised metered dose inhaler (pMDI), or inhalation of powdered drug, generally admixed with an excipient, from a dry powder inhaler (DPI). Following strong concern about the link between depletion of the earth's ozone layer and chlorofluorocarbon (CFC) emissions, the use of these materials in pressurised inhalers is being phased out and interest in DPI systems has been stimulated.
Most DPIs use either bulk powder reservoirs or individual pre-measured doses. There are, however, problems associated with accurately metering a measured small quantity (e.g. 500 micrograms or less) of powder either from a bulk reservoir within an inhaler or into a capsule or blister. With many drugs, e.g. potent drugs, this introduces the necessity to add excipients, such as lactose powder, to significantly increase the quantity of powder to be metered. Such excipients are however generally undesirable as they can pose subsequent powder deagglomeration problems and can cause dryness and other unwanted effects in the patient's mouth.
Dry powder inhalers in which predetermined doses of medicament are dispensed from a sheet material including discrete microdepressions (having a depth of about 5 to 500 micron and an opening at the surface of the sheet material of about 10 to 500 micron in width) filled with medicament are disclosed in U.S. Pat. Nos. 5,408,994, 5,437,271, 5,469,843, 5,482,032, and 5,655,523.
Various methods for coating powders on to substrates are known. Typical of those under consideration for use in drug delivery applications are the electrostatic coating methods disclosed in U.S. Pat. Nos. 4,197,289, 5,699,649, 5,960,609, 6,146,685, 6,319,541 and 6,652,903, and US patent application US200210085977. Such methods tend to be complex, slow, and difficult to control.
Other methods of coating powders onto moving web substrates include fluidized bed methods, for example as disclosed in U.S. Pat. Nos. 4,088,093 and 6,037,019, spraying methods (e.g. U.S. Pat. Nos. 4,288,521 and 5,897,746), suction methods (e.g. U.S. Pat. No. 4,313,972), magnetic methods (e.g. U.S. Pat. No. 4,470,350), and sprinkling methods (e.g. U.S. Pat. Nos. 4,209,553 and 5,415,717). A method of depositing suspended particles onto a substrate for use in inhalation devices, involving suspending agent evaporation, is disclosed in U.S. Pat. No. 5,503,869. However, none of these various methods is well suited to the accurate metering of pharmaceutical powders into microdepressions on a surface of a web.
WO patent application 95/21768 describes a process for filling blister cavities with powder whilst they are mounted on a continuous web. An oscillating and rotating system is provided to break down aggregates in the 0.1 to 10 mg powder doses. Such large masses of powder are very many times greater than the small quantities of powder that the micro-depressions tape based inhalers described in the aforementioned patents are intended to deliver.
U.S. Pat. No. 5,192,548 discloses a method of coating micronized drug onto a closed loop of sheet material including microdepressions on its top-side in which micronized drug is fed onto the sheet material, rollers assist in spreading micronized drug over the surface of the sheet material and curved slats function to smear the micronized drug out over the surface of the sheet material. One roller is shown with a flattened portion intended to help prevent drug from building up behind it.